Enhancing survival in locally advanced esophageal cancer: a comparative analysis of neoadjuvant immunotherapy versus conventional neoadjuvant therapies using the SEER database

Introduction

Esophageal cancer (EC) is a significant contributor to mortality among gastrointestinal malignancies (1). According to 2020 statistics, EC ranks as the sixth leading cause of cancer-related deaths worldwide, accounting for approximately 544,000 deaths, or 3.1% of all cancer fatalities (2). EC is primarily classified into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (3), each with distinct epidemiological features and risk factors. While adenocarcinoma is predominant in Western regions, ESCC accounts for over 90% of EC cases in East Asia, including China, and the Middle East (4). The current therapeutic strategies for EC involve a multimodal approach, incorporating surgery, radiotherapy, chemotherapy, and immunotherapy. For early-stage cancers detected with superficial lesions, surgical intervention is preferred. However, most EC patients are diagnosed at locally advanced or metastatic stages due to typically atypical early clinical presentations, precluding direct surgical interventions and resulting in poor 5-year survival rates of 15–20% (5).

Both the Chinese Society of Clinical Oncology (CSCO) and the National Comprehensive Cancer Network (NCCN) guidelines recommend neoadjuvant therapy combined with radical surgery to enhance survival rates in patients with locally advanced EC (6). Currently, neoadjuvant treatments predominantly include neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (NCRT) (7). Based on the findings from the CROSS and NEOCRCTE5010 trials (8,9), NCRT followed by surgery has emerged as the established standard approach for the management of locally advanced EC, boasting a pathological complete response (pCR) rate exceeding 40%. Furthermore, the JCOG9907 trial has provided robust evidence demonstrating that NCT yields comparable overall survival (OS) and progression-free survival outcomes to NCRT, thereby consolidating NCT as the preferred modality for the treatment of locally advanced ESCC (10). Despite these considerable advancements, it is noteworthy that long-term survival rates for patients subjected to either NCRT or NCT in conjunction with radical esophagectomy remain suboptimal (11). Thus, there is an urgent need to identify novel neoadjuvant treatment modalities that enhance tumor response and survival, minimize surgical impact, and ensure favorable safety profiles.

Programmed cell death protein 1 (PD-1) and its ligands have emerged as pivotal regulators of tumor-induced immune suppression. Tumor cells elude immune surveillance and foster tumor growth and metastasis by upregulating programmed death-ligand 1 (PD-L1) expression, thereby impeding the immune system’s attack on the tumor. Inhibiting the PD-1/PD-L1 pathway with PD-1 or PD-L1 inhibitors restores T-cell activity, augmenting anti-tumor immune responses. This approach has demonstrated notable efficacy across various tumor types, including EC (12,13). Presently, the combination of immunotherapy with chemotherapy has become the frontline treatment for advanced EC, exhibiting promising disease control outcomes (14,15). Radiotherapy, an integral facet of EC management, is believed to harbor synergistic potential when coupled with immunotherapy (16). The clinical significance of immunotherapy in the context of advanced EC has been acknowledged by NCCN guidelines (17). Leveraging these promising outcomes, numerous clinical trials have embarked on investigating the efficacy and safety of neoadjuvant immunotherapy (NAI) in locally advanced EC, encompassing modalities such as nCT immunotherapy and NCRT immunotherapy (18-20). However, the evidence supporting the efficacy of incorporating immunotherapeutic agents into conventional neoadjuvant therapy (CNAT) for locally advanced EC is still scarce, underscoring the need for further investigation. Consequently, it is crucial to conduct additional studies to examine the combination of NAI with radical surgery in this patient population. Such research is essential to substantiate the potential benefits of this therapeutic strategy and to inform clinical decision-making and the design of future clinical trials.

Given the high incidence and relatively poor prognosis of locally advanced EC, as well as the limited research on immunotherapy for such patients, we conducted an in-depth analysis using the Surveillance, Epidemiology, and End Results (SEER) database, maintained by the National Cancer Institute (NCI). The primary aim of this study was to assess whether NAI combined with surgical intervention could significantly improve survival benefits for patients with locally advanced EC. Specifically, our focus was on the impact of this combined treatment on OS and cancer-specific survival (CSS) rates. By further exploring significant prognostic factors affecting this patient group, this study seeks to provide additional evidence for decision-making in clinical practice and to offer more reference data for the design of future clinical trials. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1905/rc).

Methods

Data sources and patient selection

The patient cohort for this study was derived from the SEER cancer database of the NCI using SEER*Stat software (version 8.4.3). This version encompasses data from 17 cancer registries spanning the years 2000 to 2020, covering approximately 28% of the U.S. population (21). The SEER database maintains strict patient confidentiality, ensuring that personally identifiable information is not disclosed. Therefore, ethical approval for data extraction from the SEER cancer database was not required, and obtaining informed consent from participants was deemed unnecessary. The first PD-1 immunotherapeutic medication to be licensed for this use was pembrolizumab, also known as K-drug, which was approved by the U.S. Food and Drug Administration (FDA) in 2019 (22). With this approval, EC officially entered the era of immunotherapy, and a number of clinical trials examined the safety and effectiveness of NAI for locally advanced EC. In line with the approval of immunotherapy as a primary treatment modality, we primarily focused on patients diagnosed with EC between 2019 and 2020 in order to assess the efficacy of NAI. Patients with diagnoses between 2004 and 2014 comprised the analysis’s comparative cohort. Data from 2000–2003 and 2015–2018 were excluded due to incomplete treatment protocols in the 2000–2003 period and the lack of standardization in immunotherapy use between 2015 and 2018, which resulted in treatment heterogeneity.

After excluding other malignant tumors, patients diagnosed with EC were identified using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) component codes (C15.1–C15.9). The diagnostic timeframes spanned from 2004 to 2014 and 2019 to 2020. The variables comprised treatment details (surgery, chemotherapy, radiotherapy), SEER-documented primary cause of death, survival time, survival status, and date of initial diagnosis; demographic data (age, sex, race, marital status); and clinical-pathological characteristics (histological type, tumor location, tumor size, pathological grade, and SEER historical staging system). The SEER staging system categorizes stages into “in situ”, “local”, “regional”, and “distant”. In this study, “local disease” referred to a tumor confined to a specific anatomical location without compromising the esophageal mucosal membrane or involving regional lymph nodes (T1–2N0M0). “Regional disease” was defined as a tumor limited to the regional anatomical area with no evidence of distant metastases (T3–4aN0M0/T1–4aN1–3M0).

Inclusion criteria were: (I) patients who underwent surgical treatment; (II) patients who received neoadjuvant therapy, including systemic therapy both before and after surgery; systemic therapy before surgery; (III) individuals aged above 18 years or below 75 years. Exclusion criteria included: (I) patients who were not suggested or denied surgical surgery, those with incomplete surgical information, or persons who died before the indicated surgical operation; (II) cases with insufficient or incomplete therapy and follow-up data, patients with a survival period of 0 days; (III) patients diagnosed with carcinoma in situ, distant metastases, or unclear metastatic status. The flowchart illustrating the selection process for the study population is presented in Figure 1.

Figure 1 The flowchart illustrating of patient selection and analysis. CNAT, conventional neoadjuvant therapy; NAI, neoadjuvant immunotherapy; SEER, Surveillance, Epidemiology, and End Results.

Additionally, we recruited 157 patients diagnosed with Locally Advanced ESCC who received neoadjuvant therapy at Zhangzhou Affiliated Hospital of Fujian Medical University and Zhongshan Hospital of Xiamen University between 2019 and 2023, as an external validation cohort. This cohort comprised 108 patients treated with neoadjuvant chemoimmunotherapy (nICT group) and 49 patients receiving nCT alone (nCT group). The commonly used chemotherapy regimen is platinum-based chemotherapy combined with paclitaxel, administered once every 3 weeks. All patients received a minimum of two cycles of treatment, with the dose adjusted according to the patient’s tolerance. In the nICT group, PD-1 monoclonal antibodies, including camrelizumab, pembrolizumab, sintilimab, tislelizumab, and toripalimab, were administered at a fixed dose of 200 mg in combination with chemotherapy. Demographic and clinical-pathological characteristics were obtained from medical records and follow-up records. The inclusion and exclusion criteria for the external validation cohort were identical to those mentioned above. This study was approved by the Ethics Committee of Zhongshan Hospital of Xiamen University (approval No. 2025-060) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, with informed consent obtained from all patients.

Study outcomes

For this investigation, locally advanced EC cases from the SEER database were divided into two groups. These categories were formed based on the time of immunotherapy approval as a primary treatment option for EC. The NAI group comprised patients receiving neoadjuvant chemotherapy (nCT) or radiotherapy in combination with immunotherapy. The CNAT group included patients treated with conventional neoadjuvant modalities such as nCT and neoadjuvant chemoradiotherapy (NCRT).

Primary endpoints of this study included OS and CSS. OS was defined as the duration from disease diagnosis to patient death or last follow-up, while CSS referred to the interval from EC diagnosis to death attributed to EC, or to the last follow-up in the absence of cancer-related death. Major pathological response (MPR) is defined as the presence of fewer than 10% live tumor cells in the excised tumor specimen. In contrast, pCR is defined by the complete absence of remaining tumor cells in both the original tumor site and the lymph nodes. The SEER Cause of Death Classification was employed to determine and document the specific cause of death for every patient. In the SEER database, the status of survival is recorded in ‘Vital status recode’, while the length of survival is documented in ’survival months’.

Statistical analysis

The statistical analysis in this study was performed using SPSS version 22.0 and R version 4.3.2. Chi-squared tests were employed to evaluate the basic clinical characteristics of patients in the NAI and CNAT groups. Given inherent differences in baseline characteristics, we employed propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to mitigate selection bias. PSM was conducted using a 1:2 technique with a caliper width of 0.01 to balance baseline covariates between groups. However, PSM can lead to a reduction in sample size and potential loss of information. Therefore, another commonly used method, IPTW, was also employed to balance the groups. IPTW maximizes available information while preserving all patient data and balances confounding factors by estimating inverse propensity scores for each subject. OS and CSS were estimated using the Kaplan-Meier method, with differences in survival assessed using stratified log-rank tests. Univariate and multivariate analyses were conducted using the Cox proportional-hazards model, and variables exhibiting P values less than 0.05 in univariate analysis were included in the multivariate analysis. A follow-up time of 23 months was chosen as the cut-off value for survival analysis. Subgroup analyses were conducted to explore potential treatment interactions. All analyses were two-tailed, with statistical significance defined as a P value less than 0.05.

Results

Baseline characteristics and adjustment of PSM and IPTW in patients with locally advanced EC

In our study, we utilized data from the SEER database maintained by the NCI, which included 3,708 patients diagnosed with locally advanced EC. These patients underwent surgical treatment following neoadjuvant treatment. The cohort was divided into two groups based on the treatment modality: NAI group and CNAT group. The initial dataset comprised 2,764 patients in CNAT group and 944 in NAI group. We analyzed demographic and clinical characteristics such as age, sex, histology, tumor location, tumor size, stage at diagnosis (summary stage), tumor grade, marital status, and race. The preliminary data showed that the majority of patients were Caucasian (90.8%), with 60.8% of patients aged ≤65 years. Males dominated the cohort, accounting for 83.3% of cases, with a male-to-female ratio of 5:1. Significant differences between the two groups included age, sex, tumor grade, summary stage, and race (P<0.05).

To adjust for potential baseline confounders and ensure comparability between groups, we employed PSM and IPTW. After these adjustments, the CNAT group consisted of 1,888 patients post-PSM and 2,831.7 post-IPTW, while the NAI group comprised 944 post-PSM and 1,428.2 post-IPTW patients. Subsequent analyses revealed that, except for differences in grade in the IPTW analysis (P=0.049), there were no statistically significant differences between the two groups in terms of age, sex, histology, tumor location, or other baseline characteristics (P values >0.05), confirming the effectiveness of our matching strategy. This initial evaluation provides a balanced foundation for further analyses to compare the efficacy of EC treatments within our study cohort. Table 1 summarizes the baseline characteristics comparison between the two groups before and after matching. Figure 2 illustrates the standardized mean differences (SMD) of variables before and after matching.

Figure 2 The standard mean differences of baseline characteristics before and after matching. SMD, standardized mean difference.

Enhanced survival outcomes with NAI in locally advanced EC

In the initial dataset, OS rates at 6, 12, 18, and 23 months demonstrated statistically significantly higher survival for the NAI group compared to the CNAT group. Specifically, OS rates for NAI were 95.7% (94.3–97.1%), 85.3% (82.6–88.1%), 77.1% (73.4–81.0%), and 72.1% (66.8–77.8%) at these respective time points, against 93.6% (92.7–94.5%), 82.6% (81.2–84.0%), 72.2% (70.6–73.9%), and 64.1% (62.3–65.9%) in the CNAT group, with significant differences (P=0.01). Moreover, CSS rates also showed significant benefits for the NAI group, with CSS at 6, 12, 18, and 23 months recorded at 96.5% (95.2–97.8%), 88.1% (85.6–90.7%), 81.6% (78.1–85.2%), and 77.2% (71.9–82.8%), compared to 95.0% (94.2–95.9%), 85.1% (83.7–86.4%), 75.3% (73.7–76.9%), and 67.8% (66.0–69.6%) for the CNAT group, with significant statistical differences (P=0.002). The consistent pattern of survival benefits with NAI was validated in the PSM and IPTW datasets, reinforcing the robustness and credibility of the results (PSM: P=0.008 for OS and P=0.003 for CSS; IPTW: P=0.009 for OS and P=0.004 for CSS). Table 2 summarizes the survival outcomes between the two groups before and after matching. Kaplan-Meier curves further corroborated these findings, indicating a significant improvement in both OS and CSS for the NAI group (P=0.01, Figure 3A; P=0.002, Figure 3B). Post-PSM analyses revealed that NAI significantly extended both OS and CSS (P=0.008, Figure 3C; P=0.003, Figure 3D), a finding supported by IPTW datasets (P=0.009, Figure 3E; P=0.004, Figure 3F).

Figure 3 Kaplan-Meier survival curves. (A) OS of patients before matching. (B) CSS of patients before matching. (C) OS of patients after propensity score matching. (D) CSS of patients after propensity score matching. (E) OS of patients after inverse probability of treatment weighting. (F) CSS of patients after inverse probability of treatment weighting. CNAT, conventional neoadjuvant therapy; CSS, cancer-specific survival; NAI, neoadjuvant immunotherapy; OS, overall survival.

Cox regression analysis of OS and CSS: evidence from original and matched datasets

We conducted univariable and multivariable Cox regression analyses on both the original and matched datasets to investigate OS and CSS, with specific results presented in Tables 3-5. Regarding the original data, univariate Cox analysis revealed associations between sex, age, summary stage, grade, and treatment modality with patients’ OS (P<0.05). Subsequently, these factors were included in the multivariate Cox regression analysis. The multivariate analysis indicated that age, summary stage, grade, and treatment modality were independent prognostic factors for OS (P<0.05). Similarly, after univariate and multivariate Cox regression analyses, summary stage, grade, tumor size, and treatment modality were identified as independent prognostic factors for CSS (P<0.05). Likewise, in the PSM dataset, both univariate and multivariate analyses revealed that sex, age, summary stage, grade, and treatment modality were independent prognostic factors for OS (P<0.05), while summary stage, grade, tumor size, and treatment modality were independent prognostic factors for CSS (P<0.05). The IPTW dataset yielded conclusions consistent with the PSM dataset. In summary, being female and receiving NAI were associated with better prognosis, while age over 65 years, tumor size exceeding 60 mm, grade III–IV, and “regional” summary stage were considered as risk factors.

In the original dataset, the NAI group exhibited a statistically significant survival benefit over the group receiving CNAT. Specifically, the hazard ratio (HR) for OS was reduced by 20% [HR =0.80; 95% confidence interval (CI): 0.70–0.97; Figure 4A], while the HR for CSS decreased by 24% (HR =0.76; 95% CI: 0.62–0.93; Figure 4B). In the PSM dataset, the NAI group showed a 21% reduction in OS risk (HR =0.79; 95% CI: 0.65–0.95; Figure 4C) and a 26% reduction in CSS risk (HR =0.74; 95% CI: 0.60–0.92; Figure 4D). In the IPTW dataset, the NAI group showed a 21% reduction in OS risk (HR =0.79; 95% CI: 0.66–0.96; Figure 4E) and a 25% reduction in CSS risk (HR =0.75; 95% CI: 0.61–0.93; Figure 4F). Thus, the protective effects of NAI on enhancing both CSS and OS have been conclusively established.

Figure 4 Forest plots displaying the multivariable analysis of prognostic factors. (A) OS of patients before matching. (B) CSS of patients before matching. (C) OS of patients after propensity score matching. (D) CSS of patients after propensity score matching. (E) OS of patients after inverse probability of treatment weighting. (F) CSS of patients after inverse probability of treatment weighting. CSS, cancer-specific survival; CI, confidence interval; CNAT, conventional neoadjuvant therapy; HR, hazard ratio; NAI, neoadjuvant immunotherapy; OS, overall survival.

Subgroup analysis reveals differential impact of NAI on survival outcomes in locally advanced EC

We performed subgroup analysis and interaction evaluations on matched and original datasets to better clarify the effect of NAI on the prognosis of patients with locally advanced EC. These analyses are illustrated in Figure 5. In the original dataset, NAI showed no significant difference in OS and CSS across eight subgroups (interaction P values >0.05). However, a notable exception was observed in the marital status subgroup, where ‘Married’ patients (OS: HR =0.68, 95% CI: 0.54–0.86, P=0.002; CSS: HR =0.60, 95% CI: 0.46–0.79, P<0.001) exhibited a significantly greater survival benefit from NAI compared to ‘Unmarried and others’ (OS: HR =1.00, 95% CI: 0.75–1.33, P>0.99; CSS: HR =0.98, 95% CI: 0.72–1.35, P=0.92) with an interaction P value <0.05. In the PSM dataset, specifically, patients with tumor sizes >60 mm (OS: HR =0.52, 95% CI: 0.32–0.85, P=0.008; CSS: HR =0.47, 95% CI: 0.28–0.79, P=0.004) experienced a more substantial survival advantage from NAI compared to those with tumor sizes ≤60 mm (OS: HR =0.94, 95% CI: 0.74–1.21, P=0.64, interaction P=0.04; CSS: HR =0.93, 95% CI: 0.71–1.23, P=0.61, interaction P=0.04); ‘Married’ patients (OS: HR =0.67, 95% CI: 0.53–0.86, P=0.001; CSS: HR =0.61, 95% CI: 0.46–0.80, P<0.001) also showed significantly greater survival benefits compared to those categorized as ‘Unmarried and others’ (OS: HR =0.99, 95% CI: 0.74–1.33, P=0.94, interaction P=0.04; CSS: HR =0.98, 95% CI: 0.71–1.35, P=0.90, interaction P=0.02). Similar conclusions were drawn from the inverse probability weighting dataset. In summary, NAI exhibited variable effects on survival outcomes across subgroups, highlighting the importance of personalized treatment approaches for locally advanced EC.

Figure 5 Forest plots displaying the results for the subgroup analyses and interaction tests of treatment-based effects. (A) OS of patients before matching. (B) CSS of patients before matching. (C) OS of patients after propensity score matching. (D) CSS of patients after propensity score matching. (E) OS of patients after inverse probability of treatment weighting. (F) CSS of patients after inverse probability of treatment weighting. CSS, cancer-specific survival; CI, confidence interval; CNAT, conventional neoadjuvant therapy; HR, hazard ratio; NAI, neoadjuvant immunotherapy; OS, overall survival.

Survival analysis of the externally validated cohort

A total of 157 patients with locally advanced ESCC (LA-ESCC) who received neoadjuvant therapy were included in this study, with 108 in the nICT group and 49 in the nCT group. The cohort consisted of 133 males (84.7%) and 24 females (15.3%), with a median age of 61.9 years (interquartile range, 56–68 years). The majority of the primary tumors were located in the middle (58.6%) or lower (31.8%) segments of the thoracic esophagus. At diagnosis, 71.3% of patients were in clinical stage III or IV. Following neoadjuvant treatment, pCR was achieved in 15.9% of patients, while 37.6% achieved a MPR. The clinical characteristics of both groups are shown in Table 6. The final follow-up date for this study was December 2024, with a median follow-up time of 35.7 months (range, 5–61.7 months).

We first evaluated the differences in OS across different postoperative pathological states. Our results show that patients in the nICT group, as well as those with pCR, MPR, ypT1–2, ypN0, and ypTNM I stages, had significantly longer OS (P<0.05, Figure 6). To further assess the survival differences between the nCT and nICT groups, we performed Cox regression analysis to identify factors influencing OS in ESCC. Univariate Cox analysis revealed that ypT stage, ypN stage, ypTNM stage, MPR, and treatment group were significant factors affecting OS (P<0.05). After including these factors in the multivariate Cox analysis, treatment group (HR: 0.466, 95% CI: 0.225–0.962, P=0.04) was identified as an independent predictor of OS, as shown in Table 7.

Figure 6 Kaplan-Meier survival curves. (A) OS of patients according to treatment group. (B) OS of patients according to ypT stage. (C) OS of patients according to ypN stage. (D) OS of patients according to ypTNM stage. (E) OS of patients according to pCR. (F) OS of patients according to MPR. MPR, major pathological response; nCT, neoadjuvant chemotherapy; nICT, neoadjuvant chemoimmunotherapy; OS, overall survival; pCR, pathological complete response; ypTNM, post-neoadjuvant pathologic tumor-node-metastasis.

Discussion

Currently, the primary treatment strategy for locally advanced EC emphasizes a comprehensive approach centered on surgery (23). While early-stage cases can often be managed through endoscopic surgery, the majority are diagnosed only after progressing to a locally advanced stage. At this point, relying solely on surgery often fails to yield substantial benefits. Therefore, neoadjuvant therapy followed by surgery has become the standard treatment protocol (24,25). Traditional neoadjuvant therapies, such as chemotherapy and chemoradiotherapy, consistently improve R0 resection rates and survival outcomes. However, despite these benefits, post-surgery recurrence remains common, leading to ongoing exploration of alternative treatment modalities (26). The emergence of immunotherapy has challenged traditional treatment paradigms, offering new therapeutic prospects.

Pivotal clinical trials such as KEYNOTE-590, CheckMate 649, ESCORT-1, and ATTRACTION-03 have established immunotherapy, either as monotherapy or in combination with chemotherapy, as the standard first-line treatment for advanced or metastatic squamous cell carcinoma of the esophagus (15,27-29). The CheckMate-577 trial specifically provided evidence that nivolumab as adjuvant therapy can enhance disease-free survival for patients with residual disease following preoperative chemoradiotherapy and subsequent R0 resection (30). These studies support the integration of immunotherapy in neoadjuvant settings, an approach currently being evaluated in trials like JCOG1804E, NICE, KEEP-G 03, ESONICT-1, PERFECT, NATION-1907, and PALACE-1 (20,31-36). These trials assess clinical outcomes and safety of various NAI strategies, including combined immunotherapy with chemoradiotherapy, immunotherapy with chemotherapy, and exclusively NAI. Despite these advances, a standardized model for neoadjuvant treatment of EC has yet to be established. Moreover, there are limited studies reporting survival data on NAI. Therefore, our research, based on the SEER database, assesses the impact of NAI on the prognosis of patients with locally advanced EC, demonstrating a significant survival advantage for those receiving combined NAI. This provides valuable insights into the treatment of EC, particularly for those who have progressed to locally advanced stages.

Our study examined a cohort of 3,708 patients diagnosed with locally advanced EC, all of whom received neoadjuvant treatment combined with surgical intervention from 2000 to 2020. Survival analysis revealed significant improvements in OS and CSS for the group treated with NAI compared to those receiving conventional therapy (P<0.05). However, the lack of relevant efficacy assessment metrics within the SEER database made it impossible to evaluate treatment responses or tumor progression thoroughly. Consequently, using data from our center, we found that among 108 patients with LA-ESCC undergoing nICT, the pCR rate was 20.4%, and the MPR rate was 46.3%. These rates are consistent with previous clinical trials involving NAI, suggesting favorable treatment efficacy and disease control. A recent real-world cohort study of 1,428 patients with locally advanced esophageal squamous cell carcinoma demonstrated significantly improved survival with nICT versus neoadjuvant chemoradiotherapy. Patients receiving nICT achieved superior 2-year OS (81.3% vs. 71.3%; HR, 1.57; 95% CI: 1.26–1.96; P<0.001) and disease-free survival (DFS) (73.9% vs. 63.4%; HR, 1.37; 95% CI: 1.11–1.69; P<0.001). These findings indicate significant survival benefits with nICT-based therapy (37). Furthermore, the phase II clinical trial, NICE, reported that nICT provided survival benefits, including a 2-year OS of 78.1% and a 2-year recurrence-free survival (RFS) of 67.9% in patients with resectable, locally advanced ESCC with multi-station lymph node metastases after a median follow-up of 27.3 months (38). Our findings corroborate prior research, demonstrating that patients undergoing nICT exhibit significantly better survival rates than those receiving only traditional neoadjuvant therapy. Moreover, single-center data analysis revealed survival rates at 12, 24, 36, and 48 months of 95.3%, 91.2%, 85.9%, and 72.4%, respectively, thereby reconfirming the benefits of combined chemoimmunotherapy. However, it is notable that patients from the SEER database receiving NAI had 12- and 23-month survival rates of 83.1% and 64.9%, respectively, which are lower than both our own research cohort and clinical trial levels. These discrepancies likely reflect significant differences in the pathological distribution of EC between the United States and China. Adenocarcinoma predominates in the U.S., whereas squamous cell carcinoma is more common in China (2). Differences in treatment responses may stem from the unique characteristics of these cancer types (39). Additionally, the disparity may be related to early cancer detection in China, facilitated by widespread endoscopic screening, unlike in the U.S., where such screening is not standard practice, potentially resulting in later-stage diagnoses (40).

In the realm of EC, a multitude of studies have demonstrated that women typically experience better prognoses than men. Kauppila et al., through a longitudinal study of patients who underwent esophagectomy for EC between 1987 and 2010, discovered that women exhibited a 27% lower relative risk of all-cause mortality compared to their male counterparts (41). Similarly, Xie et al. reported that women with locally advanced EC have higher OS and CSS rates than men (22). Our analysis, utilizing data from the SEER database, corroborates these findings, showing significantly better OS rates for women than for men in matched samples. This gender disparity can be attributed to several factors: Firstly, major risk factors for EC such as smoking and heavy alcohol consumption are more prevalent among men. These lifestyle factors likely exacerbate the severity of the disease and adversely affect prognosis in males. Secondly, research indicates that androgens play a critical regulatory role in the sustained inflammatory response of tumors driven by unhealthy lifestyles and may influence the biological behavior of the disease (42).

In our study, univariate and multivariate Cox regression analyses of the SEER cohort data unequivocally established that age is an independent predictor of OS in patients with EC. This finding is consistent with previous research by Qiu et al., which indicated that patients over 70 diagnosed with stage I–II EC have significantly shorter OS compared to younger patients (43). The discrepancy can be attributed to several factors: older patients often suffer from multiple chronic diseases, such as cardiovascular disease and diabetes, which can interfere with the efficacy of cancer treatments and overall health, adversely affecting prognosis. Additionally, physiological decline in older patients typically results in reduced tolerance to intensive chemotherapy or radiotherapy, limiting the use of the most effective treatments (44). These findings highlight the necessity of considering age in the treatment planning and management of EC to optimize therapeutic outcomes and improve patient survival.

Pathological factors are closely associated with prognosis. Our study demonstrates that tumor size, pathological grade, and SEER summary stage significantly influence outcomes. Specifically, tumors exceeding 60 mm, those classified as grade III–IV, or staged as “regional” are correlated with poorer prognoses. Larger tumors typically indicate more advanced cancer progression and a higher likelihood of invading nearby tissues and organs (45), which complicates surgical removal and increases the risk of residual disease postoperatively. High-grade tumors (grades III–IV) exhibit greater aggressiveness and poorer differentiation (46), leading to rapidly proliferating cells that reduce the efficacy of treatments. Additionally, tumors staged as “regional” suggest that cancer has begun to spread beyond the original tumor site to nearby lymph nodes or tissues, which complicates the prospects for curative treatment. The presence of these high-risk factors is associated with reduced life expectancy, underscoring the importance of recognizing these characteristics for prognosis and treatment planning.

To further evaluate the impact of NAI on the survival rates of patients with locally advanced EC, we conducted subgroup analyses and interaction assessments. The results showed that in both the original and matched datasets, married patients experienced significantly better survival benefits from NAI compared to unmarried patients and others (interaction P values <0.05). This finding is supported by several factors: firstly, married patients typically receive greater emotional support and practical assistance from spouses and families, enhancing their overall psychological health (47); secondly, they often maintain a higher quality of life, including better dietary habits, a regular lifestyle, and consistent attention to health conditions (48); lastly, the financial stability often associated with being married can lead to higher treatment adherence (49). Additionally, our analysis revealed that patients with tumors larger than 60 mm derived greater benefits from NAI (interaction P values <0.05). This observation could be explained by the fact that smaller tumors, being less aggressive and less likely to metastasize, often have a higher baseline survival rate, which might diminish the relative survival benefit observed from the treatment. Conversely, larger or more advanced tumors typically display more complex and aggressive biological behaviors, leading to poorer prognoses without treatment (50). Consequently, additional NAI could provide significant survival benefits to these patients. Furthermore, in cases of larger tumors, higher levels of immune cell infiltration and tumor antigen expression might enhance the immune system’s response to treatment. Therefore, when considering treatment strategies, especially in the field of immunotherapy, tumor size and the level of social support are crucial considerations for clinicians.

As a retrospective study based on database analysis, there are several inherent limitations in this study. Firstly, the SEER database, while comprehensive, only encompasses data from various regions of the United States. These regions may not represent the broader national or international population, potentially limiting the generalizability of our findings. Secondly, the SEER database lacks detailed treatment information, such as the specifics of surgical procedures, types of medications used, duration of treatment regimens, completeness of treatment, and the sequence of therapeutic interventions. Thirdly, the relatively short follow-up periods for patients undergoing immunotherapy for EC within the SEER data impede a robust assessment of long-term survival outcomes. Fourthly, while the database does record survival status and duration, it omits detailed prognostic information, including data on disease recurrence, metastasis, and assessments of patient quality of life. Finally, the database does not capture potential prognostic factors that could influence outcomes, such as biomarkers, family history, nutritional status, underlying diseases, and histories of smoking or alcohol use. These limitations underscore the need for cautious interpretation of the study results and highlight areas for future research enhancements.

Conclusions

In conclusion, our study demonstrates that NAI, when combined with surgical intervention, significantly enhances survival in patients with locally advanced EC. This approach shows substantial improvements in both OS and CSS compared to conventional neoadjuvant therapies. These findings establish a solid groundwork for future research. However, the impacts on long-term survival and recurrence remain undetermined due to the short the follow-up period and the incompleteness of the follow-up data. To confirm and refine these results, further studies involving large-scale multicenter randomized controlled trials and extended follow-up periods are necessary.

Acknowledgments

We acknowledge the efforts of the SEER Program in providing the valuable data used in this study. Without their dedication to data collection and dissemination, this research would not have been possible.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1905/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1905/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1905/prf

Funding: This work was supported by the Health Committee of Fujian Province (grant No. 2022QNA095).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1905/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of Zhongshan Hospital of Xiamen University (approval No. 2025-060) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, with informed consent obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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